Antibody-based therapy for cancer has become an established strategy for treating patients with different kinds of tumors. Antibody-based therapy uses specially engineered human antibodies to bind specifically and tightly to molecular targets present on the surface of tumors. Using modern techniques it is possible to create a human antibody specific to almost any extracellular/ cell surface target. These therapeutic antibodies are in many ways indistinguishable from the natural antibodies the body makes to fight viral and bacterial infections. This is one of the reasons they are an exceptionally well tolerated drug with very few toxic side effects.
Different types of antibodies are being developed for the clinic. Almost all therapeutic antibodies are of the IgG subtype. The IgG “backbone” consists of 2 identical copies of the heavy and the light chains, which are schematically depicted as a Y-shape. The N-terminal region of the light and heavy chains each have a domain known as the variable region which forms the antigen binding site of the molecule. The specificity of an antibody is based on the affinity of the antigen binding site of the antibody (paratope) to a specific region of the target molecule (epitope). A bispecific antibody differs from conventional therapeutic antibodies because it has two different antigen binding sites and consequently binds to two different antigens or epitopes. Many different types or formats of bispecific antibodies have been experimentally created. Biclonics® is the proprietary bispecific antibody format of Merus. Biclonics® are full length IgG bispecific antibodies encoded by a common light chain and two different heavy chains. Through their ability to bind to two different epitopes on a single or on multiple target antigens, bispecific antibodies can often exert more potent biological activities than conventional therapeutic antibodies. They have the ability to bind target cells more specifically and therefore are useful for drug conjugate technologies. They can also be applied to redirect immune effector cells such as T cells or NK cells for potent target cell killing.
There are a number of ways that therapeutic antibodies can exert their anti-tumor activity. In general they are targeted to surface molecules known to have a role in cancer initiation and progression (e.g. EGFR and HER2). Therapeutic antibodies are often designed to block surface receptor cutting off the tumor promoting activity of the target. Another way antibodies can exert their effect is by rapidly removing the receptor or target from the cell surface. In humans natural antibodies that protect against bacterial infection work mainly by attracting immune cells that then attack the pathogen by releasing toxic agents. Therapeutic antibodies can also be engineered to exploit this mechanism to attack tumor cells in the same way. Finally therapeutic antibodies can be linked to cytotoxic drugs or radioisotopes. In this way they are able to more effectively target chemotherapy or radiation therapy to tumor sites in the body reducing harmful side effects and toxicities.